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The implications of extranodal extension (ENE) in oral carcinoma have been often related to prognosis and survival rates. The clinicopathologic predictive factors of this established prognostic factor were analyzed in this retrospective study. A total of 358 medical records of a single institution were screened. Primary outcome variable was ENE. Predictor variables were clinical tumour (cT) and nodal (cN) staging, tumour subsite, and pathologically tumour size, depth of invasion (DOI), lymph node ratio (LNR), presence, or absence of perineural invasion (PNI), lymphovascular invasion (LVI) and mandibular involvement. After scrutinization, 216 records met the inclusion and exclusion criteria. Presence of ENE was noted in 42.1% (91/216) of patients. In cN0 necks ENE was 34.7% which was statistically significant. The cut-off value for tumour size, DOI and LNR were, 7.28 cm, 9 mm and 0.05 with accuracy rates of 68%, 79% and 94% respectively. The odds of presence ENE were highest with bone involvement (2.91) followed by PNI (2.34) and lastly LVI (2.17). In conclusion, these predictive factors can be used to fortify the pathologic diagnostic criteria of ENE. [ABSTRACT FROM AUTHOR]

Background: Evaluate whether extranodal extension (ENE) extent impacts outcomes in patients with oral cavity squamous cell carcinoma (OCSCC). Methods: From an institutional database, patients with OCSCC and pathologic ENE who received adjuvant treatment were included. Surgical slides were reviewed to confirm ENE extent. Multivariable Cox regression was used to relate patient/treatment characteristics with disease‐free survival (DFS) and overall survival (OS). ENE was analyzed as both a dichotomous and continuous variable. Results: A total of 113 patients were identified. Between major (>2 mm) versus minor ENE (≤2 mm), there was no significant difference in DFS (HR 1.18, 95%CI 0.72–1.92, p = 0.51) or OS (HR 1.17, 95%CI 0.70–1.96, p = 0.55). There was no significant association between ENE as a continuous variable and DFS (HR 0.97 per mm, 95%CI 0.87–1.4, p = 0.96) or OS (HR 0.96 per mm, 95%CI 0.83–1.11, p = 0.58). Conclusion: No significant relationship was seen between ENE extent and DFS or OS in individuals with OCSCC. [ABSTRACT FROM AUTHOR]

Lymph node metastases (LNM) play a central role in the tumour–node–metastasis (TNM) classification for colorectal cancer (CRC), with extranodal extension (ENE) as an adverse feature. ENE has never been directly compared to tumour deposits (TD). The aim of this study was to perform an up‐to‐date systematic review, including a network meta‐analysis to compare their prognostic value. A comprehensive search was conducted on PubMed, Embase, Web of Science and Cochrane databases to identify all prognostic studies on ENE and TD. A total of 20 studies were included, with 7719 cases. The primary outcome was 5‐year disease‐free survival (DFS); secondary outcomes were overall survival (OS) and disease‐specific survival (DSS). Frequentist paired and network meta‐analyses were performed using the netmeta package in R. For univariable DFS analysis, LNM + TD+ cases had a significantly worse outcome compared with LNM + ENE+ cases [hazard ratio (HR) = 1.27, 95% confidence interval (CI) = 1.06–1.53], which was no longer significant for multivariable DFS analysis (HR = 1.13, 95% CI = 0.87–1.46). All OS and multivariable DSS analyses showed a significantly worse outcome for LNM + TD+ cases compared with LNM + ENE cases. For all outcomes, both LNM + TD+ and LNM + ENE+ had a significantly increased hazard compared with LNM+ cases. This study shows that there is a trend towards worse outcome for LNM + TD+ than LNM + ENE+, not statistically significant in multivariable DFS analysis. Both groups perform significantly worse than cases with LNM only. To improve the accuracy of CRC staging, we recommend to put more emphasis on both ENE and TD in the TNM classification, with the most prominent role for TD. [ABSTRACT FROM AUTHOR]

Objectives: The presence of lymphovascular invasion (LVI), perineural invasion (PNI) and extranodal extension (ENE) have shown adverse outcomes in oral squamous cell carcinoma (OSCC). This study evaluated the impact of LVI, PNI and ENE, individually and in combination, on survival outcomes in OSCC. Material and Methods: A retrospective analysis of a prospectively maintained oral cancer database was done from January 2017 to March 2023. All consecutive OSCC patients who underwent curative intent surgery were included. The triple-positive group was defined by the presence of all three features (LVI/PNI/ENE), while the double-positive group had the presence of two features. The disease-free survival (DFS) and overall survival (OS) analysis was done between different study groups. Results: A total of 255 patients were included in the analysis. The LVI, PNI and ENE positivity was 13%, 26% and 11%, respectively. There were 19 patients (7%) with double-positive and ten patients (4%) with triple-positive disease. The triple-positive group had lower DFS than non-triple-positive (0% vs 57%, p-value 0.001) and lower OS (0% vs 72%, p-value 0.003). The median DFS and OS of the triple-positive group were eight months and 24 months, respectively. Similarly, the double-positive group also had statistically significant inferior DFS (p-value 0.007) and OS (p-value 0.002) compared to the single-positive/triple-negative group. Conclusion: The triple-positive disease had poor outcomes, with no patients achieving disease-free or overall survival at the 5-year follow-up. The presence of multiple adverse factors necessitates modification of adjuvant therapy and therapeutic strategy, which may enhance survival outcomes. [ABSTRACT FROM AUTHOR]

Background/Purpose: Extranodal extension (ENE) is an established prognostic factor in various malignancies, affecting survival in pancreatic head cancer (PHC). However, its significance in pancreatic body/tail cancer (PBTC) remains unclear. Therefore, we aimed to investigate the impact of ENE on PTBC prognosis. Methods: We analyzed data collected from electronic medical records of patients with PBTC who underwent distal pancreatectomy at a single center between January 2011 and December 2015. The patients were categorized based on ENE presence and prognostic implications were evaluated using Kaplan–Meier survival curves and Cox proportional hazards model. Results: PBTC cases involving lymph node (LN) metastasis and ENE exhibited significantly lower disease‐free (DFS) and overall survival (OS) rates compared to cases without LN metastasis or ENE (median DFS; N0, 23 months; LN+/ENE−, 10 months; LN+/ENE+, 5 months; p <.001). No statistically significant difference was observed in DFS and OS rates between patients with N1/N2 in the group without ENE and those with ENE+. Multivariate analysis confirmed ENE as a significant adverse prognostic factor. Conclusions: ENE significantly predicts poor prognosis in PBTC, particularly in cases with nodal metastasis. The current cancer staging system for PBTC should incorporate ENE status. Moreover, different staging systems should be considered for PHC and PBTC. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the rates and patterns of distant metastasis in head and neck SCC at the time of presentation and to study the association between distant metastasis with pre-treatment, clinical, and pathological predictors of outcomes. Method: This is a retrospective study conducted in a tertiary care hospital. All patients with primary head and neck squamous cell carcinoma that had been evaluated at our institute between October 2018 and December 2020 were included in the study. Various clinical data were analysed and pattern of metastasis was studied. Result: Ten per cent (50 cases) of 501 studied patients had distant metastasis. The most common site of distant metastasis was lung. The rate of distant metastasis was high in patients with poorly differentiated cancers. By Kaplan–Meier analysis, the median survival duration after diagnosis of metastasis was four months. Conclusion: The rate of distant metastasis was 10 per cent in the study. Patients with poorly differentiated tumours, locally advanced primary lesions, higher nodal stage, particularly with extra nodal extension, and hypopharyngeal primary, tend to exhibit increased risk for distant metastasis at the time of presentation. [ABSTRACT FROM AUTHOR]

Abstract Background Lymph node (LN) status is an important prognostic factor for parotid gland cancer (PGC). This study aimed to analyze the impact of extranodal extension (ENE) of intraparotid LN and LN metastasis burden on survival in PGC. Methods Patients with surgically treated PGC and at least one metastatic cervical LN were retrospectively enrolled. Primary outcome variables were distant metastasis-free survival (DMFS), disease-specific survival (DSS), and overall survival (OS). The impact of ENE and LN metastasis burden was assessed using the Cox model. Results A total of 292 patients were included. ENE in cervical or intraparotid LN was not associated with DMFS, DSS, or OS. Intraparotid LN metastasis had a significant impact on prognosis, and the presence of only one metastatic intraparotid LN offered an approximately 1.5-fold risk of distant metastasis. Prognostic models based on the number of positive LNs (1 vs. 2–3 vs. 4+) were superior to the AJCC N stage in terms of DMFS, DSS, and OS. Conclusions ENE of cervical or intraparotid LN has a limited effect on the prognosis of PGC, and the number of positive LNs is better than the AJCC N stage in LN status evaluation.

Background: Multiple factors contribute to recurrences in differentiated thyroid cancers (DTC). Though the nodal size and number of positive nodes along with the presence of extranodal extension (ENE) have been mentioned in the present ATA risk stratification, the weightage given for ENE seems inadequate compared to the former two. Methodology: Factors predicting recurrences were analysed in this retrospective study of patients with DTC operated in a tertiary care centre. Based on our findings, we propose a modification in the present risk stratification. We have done so by comparing with existing risk stratification for fit and discrimination of this system. Results: Out of 1428 patients, 859 (60.2%) patients had pathological nodal metastases (pN +) with ENE being present in 26.8% of these. The recurrence rate was 6.4% (92 patients). Recurrence rates in patients with ≤ 5 nodes without ENE, > 5 nodes without ENE, ≤ 5 nodes with ENE and > 5 nodes with ENE were 2.7%, 1.3%, 8.3% and 10.3%, respectively. Recurrence rates in patients with 0.2–3 cm without ENE, 0.2–3 cm with ENE and > 3 cm with/without ENE were 1.8%, 8.5% and 13.4%, respectively. A modified risk stratification incorporating ENE and excluding the number of metastatic nodes was proposed. The modified risk stratification had a better fit than the present system in terms of higher C index and lower AIC. Conclusions: Extranodal extension in differentiated thyroid cancer had the maximum influence on recurrence risk (recurrence-free survival) in our cohort. The prognostic impact of ENE supersedes the number of positive nodes in the risk of recurrence. [ABSTRACT FROM AUTHOR]

Objective: Although large retrospective database studies have associated extranodal extension (ENE) with worse survival in several head and neck cancers, the prognostic significance of ENE in laryngeal squamous cell carcinoma (LSCC) remains unclear. Our study examines ENE and overall survival (OS) in LSCC. Methods: The 2006–2017 National Cancer Database was queried for patients with LSCC undergoing surgical resection and neck dissection, with or without adjuvant therapy. Kaplan–Meier and multivariable Cox regression survival analyses were implemented to identify the independent impacts of pathologic nodal (pN) classification and ENE on OS. Results: Of 4208 patients satisfying inclusion criteria, 2343 (55.7%) were pN0/ENE‐negative, 1059 (25.2%) were pN1‐2/ENE‐negative, and 806 (19.2%) were pN1‐2/ENE‐positive. The 5‐year OS of pN0/ENE‐negative, pN1‐2/ENE‐negative, and pN1‐2/ENE‐positive patients was 62.8%, 56.7%, and 32.9%, respectively (p <.001). Among pN1‐2/ENE‐positive patients undergoing no adjuvant therapy, adjuvant radiotherapy alone, and adjuvant chemoradiotherapy, 5‐year OS was 24.1%, 30.7%, and 36.7%, respectively (p <.001). After adjusting for patient demographics, clinicopathologic features, and adjuvant therapy, ENE‐positivity was associated with worse OS than ENE‐negativity (adjusted hazard ratio [aHR] 1.76, 95% confidence interval [CI] 1.53–2.02, p <.001). pN1/ENE‐positivity (aHR 1.82, 95% CI 1.31–2.54) and pN2/ENE‐positivity (aHR 1.89, 95% CI 1.49–2.40) were associated with worse OS than pN1/ENE‐negativity (p <.001). Microscopic (aHR 1.83, 95% CI 1.54–2.18) and macroscopic ENE‐positivity (aHR 1.75, 95% 1.35–2.26) were associated with worse OS than ENE‐negativity (p <.001). Conclusion: ENE‐positivity has prognostic significance in LSCC and is associated with worse OS than ENE‐negativity. pN classification did not have prognostic significance independent of ENE. ENE should be carefully considered when determining the prognosis of LSCC and selecting adjuvant therapy. Level of Evidence: 4. [ABSTRACT FROM AUTHOR]

Extranodal extension (ENE) is strongly associated with worse outcomes in patients with head and neck squamous cell carcinoma (HNSCC) and is included in staging systems for HNSCC2,3. While histopathological determination remains the gold standard, pathologic confirmation is not always available for every patient or may not be available at the time when evidence of ENE may alter the treatment plan. This study aims to develop an automated method of pre-treatment radiographic imaging ENE (iENE) detection without human intervention to increase the chances of clinical adoption and improve risk stratification of patients with ENE. In a previous study by Kann et al, a deep learning model was used to predict the presence of iENE in pre-treatment computed tomography (CT) scans of lymph nodes (LNs) cropped along their borders1. The model trained on 2673 LNs from 270 patients achieved a notable AUC score of 0.91 on the held-out test set, and 0.84 when tested on multi-institutional data. This performance gap may be attributed to the strong correlation between ENE status and LN diameter, as revealed by their regression analysis of clinical variables. Additionally, deploying their model in clinical settings necessitates substantial human involvement, as it requires contouring single or multiple suspicious LNs for inference. To address these issues, we introduce a deep learning model designed to predict patient-level ENE without LN segmentations. Not relying on manual segmentation or cropping along the LNs borders improves potential adoption and serves as a regularization technique to reduce feature correlation with LN volume. We utilized a retrospective dataset comprising 922 oropharyngeal cancer patients and their radiotherapy (RT) treatment planning CT scans, each annotated by a radiologist for the presence of iENE. Our model analyzes 256x256x128 voxels centered around the larynx, encompassing LNs across all neck levels. Due to the input's considerable size, conventional 3D convolutional neural networks proved inefficient due to GPU memory limitations. To circumvent this, we leveraged ACS convolutions (ACSConv), which adapt 2D convolutions for 3D volumetric images, allowing us to capitalize on ImageNet pre-trained weights for more robust feature learning and quicker convergence. Our dataset was divided into 759 cases for training and 163 for held-out testing, with the date of diagnosis as the separation point, simulating a pseudo-prospective in-silico trial. The model was trained across four cross-validation folds on the training set, and the results from these four models were ensembled during inference. Our ACSConv models, without pre-training, achieved an area under the receiver operating characteristic curve (AUROC) of 0.80-0.83 and an area under the precision-recall curve (AUPRC) of 0.47-0.61 on the held-out test set, whereas our ImageNet pre-trained ACSConv model improved with an AUROC of 0.87-0.91 and an AUPRC of 0.52-0.69. This highlights the benefit of using ImageNet pre-trained weights, which encapsulate robust features learned from millions of standard images. However, it's crucial to recognize that these performance metrics solely gauge the model's alignment with iENE, not histopathology. To demonstrate the model's risk stratification capabilities, we examined overall survival using Kaplan-Meier curves. The radiologist's iENE determination did not yield a statistically significant difference (p=0.01), whereas the model's predictions resulted in significant differences (p<0.005). The increased prognostic power may be attributed to inherent limitations of radiological determination compared to histopathology. Alternatively, the model may be less sensitive and highlight severe cases, increasing its prognostic power. External validation on unseen cohorts will further elucidate the model's prognostic capabilities and limitations. [Display omitted] Additionally, we assessed the model's predictions against the volume of the largest LN gross tumor volume (GTVn) and found a moderate Spearman's correlation coefficient of 0.531. This suggests that while the model does consider GTVn volume, it certainly incorporates information beyond LN borders, potentially shedding light on issues with GTVn determination. [Display omitted] To account for potential variability in larynx segmentation models, we explored the impact of test-time augmentations on model inference. This simulated variations in larynx segmentation and its effect on iENE model performance. Notably, we observed no significant differences in prediction standard deviations between patients with or without iENE. An interesting trend emerged, showing that prediction standard deviations increased as the model's confidence decreased (closer to 0.5). This underscores the necessity for a deeper investigation into deep learning model behaviors to enhance safety and increase the likelihood of clinical adoption. [Display omitted] Our study presents a novel deep learning model for the automated detection of pre-treatment iENE. With improved performance and prognostic capabilities, this model holds potential for enhancing risk stratification in HNSCC patients and merits further validation on external datasets and in clinical practice. [ABSTRACT FROM AUTHOR]

Background: For oral cavity squamous cell carcinoma (OSCC), extent of extranodal extension (ENE) (minor, ≤2 mm; major, >2 mm) is differentially prognostic, whereas limitations exist with the 8th edition of American Joint Committee on Cancer/International Union Against Cancer TNM N‐classification (TNM‐8‐N). Methods: Resected OSCC patients at four centers were included and extent of ENE was recorded. Thresholds for optimal overall survival (OS) discrimination of lymph node (LN) features were established. After dividing into training and validation sets, two new N‐classifications were created using 1) recursive partitioning analysis (RPA), and 2) adjusted hazard ratios (aHRs) and were ranked against TNM‐8‐N and two published proposals. Results: A total of 1460 patients were included (pN0: 696; pN+: 764). Of the pN+ cases, 135 (18%) had bilateral/contralateral LNs; 126 (17%) and 244 (32%) had minor and major ENE, and two (0.3%) had LN(s) >6 cm without ENE (N3a). LN number (1 and >1 vs. 0: aHRs, 1.92 [95% confidence interval (CI), 1.44–2.55] and 3.21 [95% CI, 2.44–4.22]), size (>3 vs. ≤3 cm: aHR, 1.88 [95% CI, 1.44–2.45]), and ENE extent (major vs. minor: aHR, 1.40 [95% CI, 1.05–1.87]) were associated with OS, whereas presence of contralateral LNs was not (aHR, 1.05 [95% CI, 0.81–1.36]). The aHR proposal provided optimal performance with these changes to TNM‐8‐N: 1) stratification of ENE extent, 2) elimination of N2c and 6‐cm threshold, and 3) stratification of N2b by 3 cm threshold. Conclusion: A new N‐classification improved staging performance compared to TNM‐8‐N, by stratifying by ENE extent, eliminating the old N2c category and the 6 cm threshold, and by stratifying multiple nodes by size. There are several limitations in the most recent TNM N classification system including categories with small sample size and categories that have limited prognostic value. The authors proposed and validated a new N classification system that overcomes these limitations and outperforms the previous iteration of TNM. [ABSTRACT FROM AUTHOR]

Extranodal extension (ENE) of lymph node metastasis in oral cancer has been well demonstrated to reflect tumor aggressiveness. However, there are few studies to show the association between ENE and tumor invasion status of metastatic lymph node. The purpose of this study is therefore to investigate pathological nodal factors including tumor invasion status of ENE-positive lymph node and its association with clinical outcomes in oral cavity squamous cell carcinoma (OSCC) patients. We identified OSCC patients with at least one pathologically ENE-positive node and measured area of metastasis within lymph node (inside metastasis), and area of metastatic lymph node. We defined tumor invasion ratio (TIR) as the ratio of inside metastasis area to metastatic lymph node area. We observed that the value of TIR had a wide variation and that metastatic lymph nodes with small TIR can develop ENE. In addition, we demonstrated that tumors with smaller TIR had significantly worse DFS (HR 3.94, [1.21–12.83]; p = 0.014), OS (HR 5.38, [1.45–19.93]; p = 0.005), and more DM (HR 10.01, [1.17–86.0]; p = 0.001) than those with larger TIR. This is the first study to evaluate the detailed tumor invasion status of lymph node with ENE and showed that smaller TIR can develop ENE which was associated with clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyze the impact of the number and extranodal extension (ENE) of positive parotid lymph nodes (LNs) on distant metastasis in parotid cancer. Methods: Patients with surgically treated parotid cancer were retrospectively enrolled. The hazard ratios (HRs) of the number and ENE of positive parotid LNs on distant metastasis-free survival (DMFS) were evaluated. Results: In the Cox model, the groups with zero and one positive LN had comparable 10-year DMFS, but those with two positive LNs had an HR of 2.11 (95% CI: 1.36-5.29), and those with three or more positive LNs had an HR of 3.31 (95% CI: 2.05-8.43). The presence of ENE in parotid LNs did not impact the DMFS (p = 0.462; HR: 2.17; 95% CI: 0.84-6.17). Conclusion: Parotid LN metastasis was associated with decreased DMFS; this effect was mainly driven by the number of positive LNs rather than ENE. [ABSTRACT FROM AUTHOR]

Purpose: The extranodal extension (ENE) in head and neck squamous cell carcinoma (HNSCC) is a potential poor prognostic factor. Clinical ENE (cENE) was incorporated in the HNSCC staging system in the 8th edition of AJCC. There is not much evidence to support the treatment of HNSCC with cN3b with radiotherapy in radical intent. This study aims to assess the treatment outcome in patients of HNSCC with cN3b disease treated with definitive radiotherapy. Method: Forty-five HNSCC patients with cN3b disease treated with definitive radiotherapy with or without concurrent chemotherapy between January 2018 to December 2018 were retrospectively evaluated. Results: The median age of the study patients was 60 years (40–75years). Only 35 patients (77.8%) could complete the prescribed course of treatment, and the leading common cause of non-completion was treatment-related toxicities. After a median follow-up period of 9.3 months (range 2–33), the median OS and PFS were 22.6 months and 7.2 months, respectively. Fourteen patients (31.1%) in our study developed grade III/IV mucositis, and 11 (24.4%) developed severe grade III/IV dermatitis. The locoregional failure constituted 24 patients (53.3%). Conclusion: The treatment outcome of HNSCC with cN3b disease is inferior. A personalized and subjective approach should be undertaken before choosing radiotherapy with a radical intent in this group of patients. [ABSTRACT FROM AUTHOR]

Oral cavity squamous cell carcinoma (OCSCC) demonstrates a high propensity to metastasize to regional lymph nodes. Despite technological and scientific advances, identification of pathological adverse features preoperatively remains elusive. This study intended to identify the true occurrence of extra-nodal extension (ENE) in clinically and radiologically N0 OCSCC patients and to investigate its impact and prognostic significance. A prospective, single-centre, non-randomized study was conducted at a tertiary cancer centre in South India to include all untreated operable patients of OCSCC without clinical, radiological, or cytological evidence of nodal metastasis (cN0). All the patients underwent tumor resection surgery with neck dissection and received adjuvant therapy when indicated. Patients were followed up and neck dissection specimens were histopathologically analyzed. The primary outcome was to assess the presence of ENE in cN0 OCSCC patients and its extent. The secondary outcomes were 2-year disease-free survival (DFS) and tumor characteristics. A total of 237 patients with operable OCSCC were evaluated. Out of these, 80 patients who were clinically and radiologically N0 were included in the study and they underwent tumor resection surgery and neck dissection. The final histopathological evaluation revealed that 21.25% of patients (n = 17) had metastatic neck disease and 7.5% of patients (n = 6) had ENE, and all were reported as microscopic ENE. Within the node-positive group, the 2-year DFS for patients with and without ENE were 50% and 90.9%, respectively (p = 0.0362). The results suggest that ENE remains a strong predictor of adverse outcomes, recurrence, and survival in oral cancer patients. [ABSTRACT FROM AUTHOR]

Abstract Objective Although large retrospective database studies have associated extranodal extension (ENE) with worse survival in several head and neck cancers, the prognostic significance of ENE in laryngeal squamous cell carcinoma (LSCC) remains unclear. Our study examines ENE and overall survival (OS) in LSCC. Methods The 2006–2017 National Cancer Database was queried for patients with LSCC undergoing surgical resection and neck dissection, with or without adjuvant therapy. Kaplan–Meier and multivariable Cox regression survival analyses were implemented to identify the independent impacts of pathologic nodal (pN) classification and ENE on OS. Results Of 4208 patients satisfying inclusion criteria, 2343 (55.7%) were pN0/ENE‐negative, 1059 (25.2%) were pN1‐2/ENE‐negative, and 806 (19.2%) were pN1‐2/ENE‐positive. The 5‐year OS of pN0/ENE‐negative, pN1‐2/ENE‐negative, and pN1‐2/ENE‐positive patients was 62.8%, 56.7%, and 32.9%, respectively (p

Abstract Background The presence of high-volume lymph node metastasis (LNM) and extranodal extension (ENE) greatly increases the risk of recurrence in patients with low-risk papillary thyroid microcarcinoma (PTMC). The goal of this research was to analyze the factors that contribute to high-risk lymph node metastasis in patients with low-risk PTMC. Methods We analyzed the records of 7344 patients who were diagnosed with low-risk PTMC and treated at our center from January 2013 to June 2018.LNM with a high volume or ENE was classified as high-risk lymph node metastasis (hr-LNM). A logistic regression analysis was conducted to identify the risk factors associated with hr-LNM. A nomogram was created and verified using risk factors obtained from LASSO regression analysis, to predict the likelihood of hr-LNM. Results The rate of hr-LNM was 6.5%. LASSO regression revealed six variables that independently contribute to hr-LNM: sex, age, tumor size, tumor location, Hashimoto’s thyroiditis (HT), and microscopic capsular invasion. A predictive nomogram was developed by integrating these risk factors, demonstrating its excellent performance. Upon analyzing the receiver operating characteristic (ROC) curve for predicting hr-LNM, it was observed that the area under the curve (AUC) had a value of 0.745 and 0.730 in the training and testing groups showed strong agreement, affirming great reliability. Conclusion Sex, age, tumor size, tumor location, HT, and microscopic capsular invasion were determined to be key factors associated with hr-LNM in low-risk PTMC. Utilizing these factors, a nomogram was developed to evaluate the risk of hr-LNM in patients with low-risk PTMC.

Abstract Background Extranodal extension (ENE) in head and neck squamous cell carcinoma (HNSCC) correlates to poor prognoses and influences treatment strategies. Deep learning may yield promising performance of predicting ENE in HNSCC but lack of transparency and interpretability. This work proposes an evolutionary learning method, called EL-ENE, to establish a more interpretable ENE prediction model for aiding clinical diagnosis. Methods There were 364 HNSCC patients who underwent neck lymph node (LN) dissection with pre-operative contrast-enhanced computerized tomography images. All the 778 LNs were divided into training and test sets with the ratio 8:2. EL-ENE uses an inheritable bi-objective combinatorial genetic algorithm for optimal feature selection and parameter setting of support vector machine. The diagnostic performances of the ENE prediction model and radiologists were compared using independent test datasets. Results The EL-ENE model achieved the test accuracy of 80.00%, sensitivity of 81.13%, and specificity of 79.44% for ENE detection. The three radiologists achieved the mean diagnostic accuracy of 70.4%, sensitivity of 75.6%, and specificity of 67.9%. The features of gray-level texture and 3D morphology of LNs played essential roles in predicting ENE. Conclusions The EL-ENE method provided an accurate, comprehensible, and robust model to predict ENE in HNSCC with interpretable radiomic features for expanding clinical knowledge. The proposed transparent prediction models are more trustworthy and may increase their acceptance in daily clinical practice.

Lymph node (LN) metastasis is an important factor in determining the treatment and prognosis of oropharyngeal squamous cell carcinoma (OPSCC). Here, we compared the somatic mutational profiles and clonal evolution of primary and metastatic LNs using multiregion sequencing of human papilloma virus (HPV)‐positive OPSCC and HPV‐negative OPSCC. We performed high‐depth whole‐exome sequencing (200×) of 76 samples from 18 patients with OPSCC (10 HPV‐positive and 8 HPV‐negative), including 18 primary tumor samples, 40 metastatic LN samples, and 18 normal tissue samples. Among 40 metastatic LNs, 22 showed extranodal extension (ENE). Mutation profiles of HPV‐positive OPSCC and HPV‐negative OPSCC were similar to those reported previously. Somatic mutations in CDKN2A and TP53 were frequently detected in HPV‐negative OPSCC. Somatic mutations in HPV‐positive OPSCC samples showed APOBEC‐related signatures. Somatic mutations from metastatic LNs showed a different pattern than the primary tumor. Somatic mutations acquired in the WNT pathway during metastasis showed a significant relationship with ENE. Clonal evolution analysis of primary and metastatic LNs showed that, in some cases, each metastatic LN originated from a different primary tumor sub‐clone.

Abstract Background Tumor deposits (TDs) are an infrequently mentioned feature of head and neck squamous cell carcinoma (HNSCC) that are currently grouped under extranodal extension (ENE) in the AJCC 8th edition of HNSCC TNM staging. The prognostic implication of TDs in comparison to ENE remains uncertain. Methods This observational, retrospective, non‐randomized study evaluated patients with HNSCC who underwent initial surgical resection, with neck dissection and adjuvant radiotherapy ± chemotherapy. Clinical variables were considered, and statistical analyses were conducted to compare time progression and overall survival (OS) in patients with TDs against those with ENE. Results Of the 71 patients included in the study, 50 were diagnosed with ENE (pN2a‐ENE in 38 patients and pN3b‐ENE in 12), while 21 had TDs ± ENE. The median time to progression was significantly different based on the presence of ENE or TDs (p = .002) and pN2a‐ENE/pN3b‐ENE or TDs (p = .007). The three‐year OS was 55.7% for the entire group, 60.4% in ENE and 38.4% in TDs (p = .021). The OS difference between the pN2a‐ENE, pN3b‐ENE, and the TDs group was also significant (p = .05). The hazard ratio between ENE and TDs was Exp (B) 4.341 (p = .044). Conclusions TDs in HNSCC are associated with a lower OS than ENE, despite intensified adjuvant therapy. Our results confirm a better prognosis for pN2a‐ENE vs. pN3b‐ENE, and pN3b‐ENE vs. TDs. TDs may serve as an indicator of poor prognosis and require separate TNM classification in HNSCC staging. Larger studies are needed to evaluate TDs impact on treatment strategies and outcomes.

Background: The presence of high-volume lymph node metastasis (LNM) and extranodal extension (ENE) greatly increases the risk of recurrence in patients with low-risk papillary thyroid microcarcinoma (PTMC). The goal of this research was to analyze the factors that contribute to high-risk lymph node metastasis in patients with low-risk PTMC. Methods: We analyzed the records of 7344 patients who were diagnosed with low-risk PTMC and treated at our center from January 2013 to June 2018.LNM with a high volume or ENE was classified as high-risk lymph node metastasis (hr-LNM). A logistic regression analysis was conducted to identify the risk factors associated with hr-LNM. A nomogram was created and verified using risk factors obtained from LASSO regression analysis, to predict the likelihood of hr-LNM. Results: The rate of hr-LNM was 6.5%. LASSO regression revealed six variables that independently contribute to hr-LNM: sex, age, tumor size, tumor location, Hashimoto's thyroiditis (HT), and microscopic capsular invasion. A predictive nomogram was developed by integrating these risk factors, demonstrating its excellent performance. Upon analyzing the receiver operating characteristic (ROC) curve for predicting hr-LNM, it was observed that the area under the curve (AUC) had a value of 0.745 and 0.730 in the training and testing groups showed strong agreement, affirming great reliability. Conclusion: Sex, age, tumor size, tumor location, HT, and microscopic capsular invasion were determined to be key factors associated with hr-LNM in low-risk PTMC. Utilizing these factors, a nomogram was developed to evaluate the risk of hr-LNM in patients with low-risk PTMC. [ABSTRACT FROM AUTHOR]

Simple Summary: Extranodal extension (ENE) represents a critical pathologic high-risk factor for disease progression in head and neck cancer. Precise pre-treatment imaging to detect the presence or absence of ENE could facilitate the selection of appropriate initial therapy. Previous studies utilizing CT or MRI for detecting ENE have shown high specificity but modest sensitivity. This study demonstrates improved image quality of cervical lymph nodes using a free-breathing MRI sequence (StarVIBE), which is highly resistant to respiratory motion. Based on node-to-node matched pathology, a composite diagnostic criterion derived from StarVIBE was proposed to potentially enhance the accurate detection of ENE. (1) Background: This study aims to evaluate the image quality of abnormal cervical lymph nodes in head and neck cancer and the diagnostic performance of detecting extranodal extension (ENE) using free-breathing StarVIBE. (2) Methods: In this retrospective analysis, 80 consecutive head and neck cancer patients underwent StarVIBE before neck dissection at an academic center. Image quality was compared with conventional VIBE available for 28 of these patients. A total of 73 suspicious metastatic lymph nodes from 40 patients were found based on morphology and enhancement pattern on StarVIBE. Sensitivity (SN), specificity (SP), and odds ratios were calculated for each MR feature from StarVIBE to predict pathologic ENE. (3) Results: StarVIBE showed significantly superior image quality, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) for enlarged lymph nodes compared to VIBE. The MR findings of "invading adjacent planes" (SN, 0.54; SP, 1.00) and "matted nodes" (SN, 0.72; SP, 0.89) emerged as notable observations. The highest diagnostic performance was attained by combining these two features (SN, 0.93; SP, 0.89). (4) Conclusions: This study confirms that StarVIBE offers superior image quality for abnormal lymph nodes compared to VIBE, and it can accurately diagnose ENE by utilizing a composite MR criterion in head and neck cancer. [ABSTRACT FROM AUTHOR]

Extranodal extension (ENE) is a pattern of cancer growth from within the lymph node (LN) outward into perinodal tissues, critically defined by disruption and penetration of the tumor through the entire thickness of the LN capsule. The presence of ENE is often associated with an aggressive cancer phenotype in various malignancies including head and neck squamous cell carcinoma (HNSCC). In HNSCC, ENE is associated with increased risk of distant metastasis and lower rates of locoregional control. ENE detected on histopathology (pathologic ENE; pENE) is now incorporated as a risk-stratification factor in human papillomavirus (HPV)-negative HNSCC in the eighth edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification. Although ENE was first described almost a century ago, several issues remain unresolved, including lack of consensus on definitions, terminology, and widely accepted assessment criteria and grading systems for both pENE and ENE detected on radiological imaging (imaging-detected ENE; iENE). Moreover, there is conflicting data on the prognostic significance of iENE and pENE, particularly in the context of HPVassociated HNSCC. Herein, we review the existing literature on ENE in HNSCC, highlighting areas of controversy and identifying critical gaps requiring concerted research efforts. [ABSTRACT FROM AUTHOR]

Objectives: The American Joint Committee on Cancer's 8th edition (AJCC‐8) separates oropharyngeal squamous cell carcinomas (OPSCCs) into human papillomavirus‐positive (HPV+) tumors and HPV‐negative tumors. Although AJCC‐8 improves prognostic prediction for survival for the majority of HPV+ OPSCC, outliers are still encountered. The goal of this manuscript is to validate the AJCC‐8 as a better metric of survivability than the AJCC‐7 in an historically under‐served rural population with confounding variables, such as tobacco use, alcohol consumption, and poor health care access and to analyze the role of extranodal extension (ENE) in this population. Design: Retrospective cohort study. Results: Compared to AJCC‐7, AJCC‐8 had a higher odds ratio (OR) for predicting mortality of stage IV HPV+ OPSCCs versus stages I–III. On multivariate analysis, HPV+ OPSCCs with ENE had a higher OR of mortality compared to ENE‐ OPSCCs. In addition, HPV+ OPSCC patients with a Charlson Comorbidity Index (CCI) > 3 had a higher OR of mortality compared to those with a CCI ≤ 3. Patients with Medicaid/self‐pay status had a higher OR of mortality compared to those with private insurance/Medicare. Finally, patients from rural populations had a higher OR of presenting with stage IV disease, a CCI > 3, and Medicaid/self‐pay status. Conclusions: Despite not being a discrete part of the AJCC‐8 staging rubric, ENE was found to have a significant impact on mortality among this population, whereas tobacco use had no effect. Rural patients were more likely to present with stage IV disease, CCI > 3, and Medicaid/self‐pay status. Stage IV disease was also associated with a higher OR of mortality. Level of Evidence: 4 Laryngoscope, 133:2621–2626, 2023 [ABSTRACT FROM AUTHOR]

Extranodal extension (ENE) is a pattern of cancer growth from within the lymph node (LN) outward into perinodal tissues, critically defined by disruption and penetration of the tumor through the entire thickness of the LN capsule. The presence of ENE is often associated with an aggressive cancer phenotype in various malignancies including head and neck squamous cell carcinoma (HNSCC). In HNSCC, ENE is associated with increased risk of distant metastasis and lower rates of locoregional control. ENE detected on histopathology (pathologic ENE; pENE) is now incorporated as a risk-stratification factor in human papillomavirus (HPV)-negative HNSCC in the eighth edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification. Although ENE was first described almost a century ago, several issues remain unresolved, including lack of consensus on definitions, terminology, and widely accepted assessment criteria and grading systems for both pENE and ENE detected on radiological imaging (imaging-detected ENE; iENE). Moreover, there is conflicting data on the prognostic significance of iENE and pENE, particularly in the context of HPV-associated HNSCC. Herein, we review the existing literature on ENE in HNSCC, highlighting areas of controversy and identifying critical gaps requiring concerted research efforts.

Survival significance of parotid lymph node (LN) factors in parotid cancer remains unclear, our goal was to assess the impact of number, size, and extranodal extension (ENE) of metastatic parotid LNs on prognosis in parotid cancer. Patients with surgically treated parotid cancer were retrospectively enrolled. Primary outcome variable was recurrence-free survival (RFS) and overall survival (OS). The hazard ratios (HRs) of main predictive variables including the number, size, and ENE of positive parotid LNs on RFS and OS were analyzed using Cox model. The secondary outcome variable was ENE of metastatic parotid LN, its association with clinicopathologic variables were evaluated using Chi-square test. In total, 453 patients (186 male and 267 female) were included. The 10-year RFS and OS rates were 73% (95%CI: 69%–77%) and 61% (95%CI: 55%–67%), respectively. In Cox model, compared none parotid LN metastasis, one metastatic parotid LN did not offer additional compromise of RFS (p = 0.224) or OS (p = 0.135), but two or more positive LNs decreased the control of RFS (HR: 2.017; 95%CI: 1.378–4.632) and OS (HR: 2.173; 95%CI: 1.367–4.275). When accounting for the number of metastatic LNs, LN size or ENE was no longer related to RFS or OS. ENE of parotid LN tended to develop if there was presence of T3/4 stage, lymphovascular invasion, high histologic grade, N2/3 stage, and three or more positive parotid LNs. Quantitative parotid LN burden but not ENE or LN size is an important determinant of survival in patients with parotid cancer. [ABSTRACT FROM AUTHOR]

Background: The study investigates the prognostic significance of lymph node ratio (LNR) on patients with head and neck squamous cell carcinoma (HNSCC) with coexistence of multiple adverse pathological features. Methods: In total, 100 patients with coexistence of perineural invasion, lymphovascular invasion, and extranodal extension of first primary HNSCC treated with radical surgery followed by adjuvant chemoradiotherapy were enrolled. Results: The optimal LNR cut‐off value for predicting overall survival (OS) and cancer specific survival (CSS) was 7%. In Cox model, we observed that LNR ≥7% was a statistically significant unfavorable predictor of OS (HR: 2.689; 95% CI: 1.228–5.889; p = 0.013) and CSS (HR: 3.162; 95% CI: 1.234–8.102; p = 0.016). Conclusion: For HNSCC patients with coexistence of multiple adverse pathological features, LNR is an independent survival predictor. Novel intensified treatments are needed for the subgroup of patients with a high LNR. [ABSTRACT FROM AUTHOR]

Simple Summary: The presence of extranodal extension is a significant prognostic factor in oropharyngeal squamous cell carcinoma. Despite its significance as a prognostic factor, the predictive efficacy of preoperative ENE outcomes falls short of clinical expectations. The aim of this study was to examine the nodal margin-related feature and nodal tumor burden-related feature to enhance the predictive power of preoperative ENE. The study revealed that the inclusion of both margin and burden-related features resulted in higher predictive power compared with the use of either feature alone in predicting ENE. It would be beneficial to incorporate nodal tumor burden assessment in addition to nodal margin evaluation to enhance the accuracy of ENE prediction. The importance of risk stratification in the management of oropharyngeal squamous cell carcinoma (OPSCC) is becoming increasingly obvious with the growing evidence of its variable prognosis. We identified and evaluated imaging characteristics predictive of extranodal extension (ENE) in OPSCC. Preoperative computed tomography and histopathologic results of 108 OPSCC patients who underwent neck dissection as primary treatment were analyzed. Imaging characteristics were reassessed for factors associated with nodal margin breakdown and metastatic burden. Moreover, the predictability of pathological ENE (pENE) was analyzed. Univariate and multivariate binomial logistic regression analyses were performed to examine the predictive power of ENE-related radiologic features. Imaging-based characteristics showed variable degrees of association with pENE. Factors associated with nodal margin breakdown (indistinct capsular contour, irregular margin, and perinodal fat stranding) and factors associated with nodal burden (nodal matting, lower neck metastasis, and presence of >4 lymph node metastases) were significantly predictive of ENE (odds ratio (OR) = 11.170 and 12.121, respectively). The combined utilization of the nodal margin and burden factors further increased the predictive ability (OR = 14.710). Factors associated with nodal margin breakdown and nodal burden were associated with pENE, demonstrating the use of combinatorial analysis for more accurate ENE prediction. [ABSTRACT FROM AUTHOR]

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Objective: To identify prognostic factors for patients with advanced persistent, recurrent, or 2nd primary oral cavity squamous cell carcinoma (OCSCC) potentially unsuitable for salvage surgery with free tissue flap (FTF) reconstruction. Materials and methods: A population-based cohort of 83 consecutive patients with advanced OCSCC who underwent salvage surgery with FTF reconstruction at a tertiary referral centre between 1990 and 2017. Retrospective uni- and multivariable analyses were performed to identify factors affecting all-cause mortality (ACM), i.e., overall survival (OS), as well as disease-specific mortality (DSM), i.e., disease-specific survival (DSS) after salvage surgery. Results: Median disease-free interval until recurrence was 15 months with recurrent stage I/II in 31% and III/IV in 69%. Median age at salvage surgery was 67 years (range 31–87) and the median follow-up (alive patients) 126 months. At 2, 5, and 10 years after salvage surgery, respectively, DSS rates were 61%, 44%, and 37% and OS rates 52%, 30%, and 22%. Median DSS was 26 and OS 43 months. Multivariable analysis identified recurrent clinical regional (cN-plus) disease [HR 3.57; p <.001] and elevated gamma-glutamyl transferase (GGT) [HR 3.30; p =.003] as independent pre-salvage predictors for poor OS after salvage, whereas initial cN-plus [HR 2.07; p =.039] and recurrent cN-plus disease [HR 5.14; p <.001] predicted poor DSS. Among post-salvage factors, extranodal extension according to histopathology [HR ACM 6.11; HR DSM 9.99; p <.001] as well as positive [HR ACM 4.98; DSM 7.51; p < 0.001] and narrow surgical margins [HR ACM 2.12; DSM HR 2.80; p < 0.01] emerged as independent factors for poor survival. Conclusion: While salvage surgery with FTF reconstruction is the primary curative option for patients with advanced recurrent OCSCC, the present findings may help guide discussions with patients who have advanced recurrent regional disease and high GGT preoperatively, especially if there is a small chance of reaching surgical radicality. [ABSTRACT FROM AUTHOR]

Lymph node (LN) metastasis is an important factor in determining the treatment and prognosis of oropharyngeal squamous cell carcinoma (OPSCC). Here, we compared the somatic mutational profiles and clonal evolution of primary and metastatic LNs using multiregion sequencing of human papilloma virus (HPV)‐positive OPSCC and HPV‐negative OPSCC. We performed high‐depth whole‐exome sequencing (200×) of 76 samples from 18 patients with OPSCC (10 HPV‐positive and 8 HPV‐negative), including 18 primary tumor samples, 40 metastatic LN samples, and 18 normal tissue samples. Among 40 metastatic LNs, 22 showed extranodal extension (ENE). Mutation profiles of HPV‐positive OPSCC and HPV‐negative OPSCC were similar to those reported previously. Somatic mutations in CDKN2A and TP53 were frequently detected in HPV‐negative OPSCC. Somatic mutations in HPV‐positive OPSCC samples showed APOBEC‐related signatures. Somatic mutations from metastatic LNs showed a different pattern than the primary tumor. Somatic mutations acquired in the WNT pathway during metastasis showed a significant relationship with ENE. Clonal evolution analysis of primary and metastatic LNs showed that, in some cases, each metastatic LN originated from a different primary tumor sub‐clone. [ABSTRACT FROM AUTHOR]

Background: Oral tongue squamous cell carcinoma (OTSCC) is a common malignancy of the oral cavity with poor survival rates. The aim of this project is to investigate the relationship between certain histopathological factors such as Worst Pattern of Invasion (WPOI) and Extranodal Extension (ENE) in patients with oral tongue squamous cell carcinoma (OTSCC) who underwent surgical resection at Loyola University Medical Center. Methods: This was a retrospective cohort study at a tertiary care academic medical center. All patients that underwent primary surgical resection of OTSCC between 1/1/2015 and 1/1/2022 were reviewed. Patients were identified using the Cerner CoPath Laboratory Information System. Results: A total of 82 patients met inclusion criteria and were included in the study. Higher grades of WPOI (WPOI 5) were not significantly associated with the presence of ENE in our study (P = 0.82), regardless of the presence of major or minor ENE. WPOI 5 was associated with a higher incidence of local recurrence (P = 0.011). Conclusions: Higher grades of WPOI were not found to correlate with the presence of ENE, a common histopathological factor that is used as an important prognostic indicator in OTSCC. It is important for clinicians to consider these factors separately when determining whether a patient is high-risk and would benefit from aggressive multimodal treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Extranodal extension (ENE) is an adverse prognostic factor for oral squamous cell carcinoma (OSCC), and patients with OSCC along with ENE require neck dissection. In this study, we developed a novel ENE histology-based pathological predictor using MMP14 expression patterns in small biopsy specimens. Methods A total of 71 surgically resected tissue, 64 dissected lymph node (LN), and 46 biopsy specimens were collected from 71 patients with OSCC. Immunohistochemical analyses of total MMP14 expression in the tumour nest and cancer-associated fibroblasts (CAFs) were performed using the MMP14 co-scoring system (high- or low-risk). The association analysis of MMP14 expression in metastatic LNs was performed with respect to the presence and absence of ENE. Clinicopathological analyses and multivariate examinations were performed to assess the risks of metastasis and ENE presence. The predictive value of ENE and the impact of ENE and MMP14 expression on 5-year overall survival were examined. Results High-risk MMP14 expression was detected in metastatic LN specimens with ENE. MMP14 expression in tumour nests and CAFs and its overexpression at the tumour–stromal interface significantly correlated with the presence of ENE. The MMP14 co-scoring system was an independent risk predictor for ENE, with sensitivity, specificity, and accuracy of over 80% in biopsy samples; patients with a high risk in the MMP14 co-scoring system had significantly worse prognoses in both resections and biopsies. Conclusion The MMP14 co-scoring system accurately predicted ENE presence and poor prognosis via immunohistochemical evaluation of small biopsies. This system is a simple, accurate, and inexpensive immunohistochemical approach that can be used in routine pathological diagnosis for effective treatment planning.

Background Lymph node metastasis (LNM) is commonly observed in papillary thyroid carcinoma. This study aimed to investigate the risk factors for LNM in patients with papillary thyroid carcinoma. Methods The clinicopathological factors of 417 patients were investigated, and differences according to the presence or absence of LNM were evaluated. Results LNM was associated with age 10 mm, multiple and bilateral tumors, tumor involving the lower pole or entire lobe, lymphovascular invasion (LVI), perineural invasion (PNI), and extrathyroidal extension (ETE). Univariable and multivariable analyses showed that age 10 mm, LVI, and ETE were related to central LNM. Male sex, tumor size >10 mm, and LVI were correlated with lateral LNM (p10 mm, multifocality, PNI, ETE, and the absence of lymphocytic thyroiditis (p10 mm, LVI, and ETE were risk factors for central LNM, while male sex, tumor size >10 mm, and LVI were risk factors for lateral LNM. ENE was more commonly observed in lateral LNM, and tumor size >10 mm, multifocal tumors, PNI, ETE, and tumors unrelated to lymphocytic thyroiditis were risk factors for ENE.

Hui-Shan Huang,1 Ming-Hsien Tsai,2– 4 Hui-Ching Chuang,2,3 Yu-Tsai Lin,2– 4 Kun-Lin Yang,2,3 Hui Lu,2 Chih-Yen Chien2,3,5 1Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 3Kaohsiung Chang Gung Head and Neck Oncology Group, Cancer Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4College of Pharmacy and Health Care, Tajen University, Pingtung County, Taiwan; 5Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, TaiwanCorrespondence: Chih-Yen Chien, Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan, Tel +886-7-7317123 ext. 2533, Fax +886-7-7313855, Email cychien3965@adm.cgmh.org.twBackground: It is well known that p16 negative oropharyngeal squamous cell carcinoma (OPSCC) has a high probability of spreading to the ipsilateral neck. However, no consensus exists as to whether to perform elective treatment for clinical nodal negative in contralateral neck.Methods: A total of 85 patients with p16 negative OPSCC who underwent primary tumor excision and bilateral neck dissections between 2005 and 2018 were analyzed retrospectively. Clinicopathologic variables were used to identify factors predicting occult contralateral nodal metastasis (OCNM). A nomogram was developed to assess the risk of OCNM and the model was validated internally by using bootstrap resampling.Results: The overall prevalence of pathologically positive contralateral nodes was 30.6% (26/85) in our cohort, and the rate of OCNM was 18.3% (11/60). The presence of ipsilateral clinical extranodal extension (cENE) was significantly associated with contralateral neck metastasis (odds ratio, 5.662; 95% CI, 2.079– 15.415) with increased risk of OCNM (odds ratio, 4.271; 95% CI, 1.045– 17.458). Moreover, the concordance index of the proposed nomogram model without ipsilateral cENE was 0.623 and could increase to 0.717 with the inclusion of ipsilateral cENE in the calculation.Conclusion: The risk of OCNM in p16 negative OPSCC with ipsilateral cENE is notable. Ipsilateral cENE-based nomogram might assist in individual decision-making regarding contralateral nodal negative neck management and help avoid the over- and under-treatment of p16 negative OPSCC.Keywords: p16, oropharyngeal cancer, occult contralateral neck metastasis, extranodal extension, nomogram

Purpose: Recurrent laryngeal nerve (RLN) invasion by extranodal extension (ENE) is a rare condition that may occur in papillary thyroid cancer (PTC), and it has never been characterised in the literature.Our research aims to investigate the clinical significance of ENE to RLN including its effect on vocal cord function, relationship with the aggressive behaviour of PTC, and optimal surgical methods. Methods: A total of 3119 patients, including 2868 patients without RLN invasion, 251 patients with RLN invasion [categorised into the ENE invasion group (n = 55) and extrathyroidal extension (ETE) invasion group (n = 196)] were analyzed retrospectively. Data on clinicopathological characteristics, vocal cord paralysis (VCP), postoperative complications, surgical methods, rates of recurrence and metastasis were collected. Predictive disease-free survival (DFS) was analysed using the Kaplan–Meier method. Results: The ENE invasion group showed a similar rate of VCP and DFS compared with the ETE invasion group (P = 0.15, P = 0.38, respectively). Sharp separation applied on the invaded nerves preserves the visual integrity of the RLN without significantly reducing the DFS (P > 0.05). ETE or ENE to RLN, lymph nodes metastasis (LNM), and T4 stage were independent factors for total recurrence [P = 0.04, hazard ratio (HR), 1.97 (1.04–3.75); P = 0.00, HR, 4.63 (2.24–9.54); P = 0.00, HR, 3.63 (1.94–6.77); P = 0.00, HR, 6.1 (3.24–11.50)]. RLN invasion, both by ETE or ENE, was significantly associated with reduced DFS (P = 0.00; P = 0.00, respectively). Conclusions: ENE to RLN, while rare, has not previously been well-studied. Our interesting premise and important findings including ENE to RLN has the same poor prognostic impact on recurrence as does invasion of the RLN by ETE and surgical management for the invaded RLN that preserves its visual integrity without compromising DFS. Those novel findings indicate that ENE to RLN could be considered as an additional factor beyond post-operative disease status and risk stratification, and it would be a valuable addition to further individualise treatment/surveillance for PTC. [ABSTRACT FROM AUTHOR]

Objectives: Accurate pre-treatment imaging determination of extranodal extension (ENE) could facilitate the selection of appropriate initial therapy for HPV-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). Small studies have associated 7 CT features with ENE with varied results and agreement. This article seeks to determine the replicable diagnostic performance of these CT features for ENE. Methods: Five expert academic head/neck neuroradiologists from 5 institutions evaluate a single academic cancer center cohort of 75 consecutive HPV + OPSCC patients. In a web-based virtual laboratory for imaging research and education, the experts performed training on 7 published CT features associated with ENE and then independently identified the "single most (if any) suspicious" lymph node and presence/absence of each of the features. Inter-rater agreement was assessed using percentage agreement, Gwet's AC1, and Fleiss' kappa. Sensitivity, specificity, and positive and negative predictive values were calculated for each CT feature based on histologic ENE. Results: All 5 raters identified the same node in 52 cases (69%). In 15 cases (20%), at least one rater selected a node and at least one rater did not. In 8 cases (11%), all raters selected a node, but at least one rater selected a different node. Percentage agreement and Gwet's AC1 coefficients were > 0.80 for lesion identification, matted/conglomerated nodes, and central necrosis. Fleiss' kappa was always < 0.6. CT sensitivity for histologically confirmed ENE ranged 0.18–0.94, specificity 0.41–0.88, PPV 0.26–0.36, and NPV 0.78–0.96. Conclusions: Previously described CT features appear to have poor reproducibility among expert head/neck neuroradiologists and poor predictive value for histologic ENE. Key Points: • Previously described CT imaging features appear to have poor reproducibility among expert head and neck subspecialized neuroradiologists as well as poor predictive value for histologic ENE. • Although it may still be appropriate to comment on the presence or absence of these CT features in imaging reports, the evidence indicates that caution is warranted when incorporating these features into clinical decision-making regarding the likelihood of ENE. [ABSTRACT FROM AUTHOR]